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The development of SARS-CoV-2 main protease (Mpro) inhibitors for the treatment of COVID-19 has mostly benefitted from X-ray structures and preexisting knowledge of inhibitors; however, an efficient method to generate Mpro inhibitors, which circumvents such information would be advantageous. As an alternative approach, we show here that DNA-encoded chemistry technology (DEC-Tec) can be used to discover inhibitors of Mpro. An affinity selection of a 4-billion-membered DNA-encoded chemical library (DECL) using Mpro as bait produces novel non-covalent and non-peptide-based small molecule inhibitors of Mpro with low nanomolar Ki values. Furthermore, these compounds demonstrate efficacy against mutant forms of Mpro that have shown resistance to the standard-of-care drug nirmatrelvir. Overall, this work demonstrates that DEC-Tec can efficiently generate novel and potent inhibitors without preliminary chemical or structural information. Conventional structure-based design of Mpro inhibitors of SARS-CoV-2 often starts from the structural information of Mpro and their binders; however, the continual rise of resistant strains requires innovative routes to discover new inhibitors. Here, the authors develop a DNA-encoded chemical library screening to produce non-covalent, non-peptidic small molecule inhibitors for SARS-CoV-2 Mpro independently of preliminary knowledge regarding suitable starting points. [ABSTRACT FROM AUTHOR]